tbuckley/cabot-search huggingface dataset:
Abstract 11851: Acetate Rescues the Gut Microbial Metabolites PAA/PAG-induced Vascular Senescence by Epigenetic and SASP Regulation
Authors: Soheil Saeedi, Aurélien Thomas, Sylvain LeGludic, Karsai Gergely, Sandra Lettlova, Elena Osto, Meret Allemann, Pratintip Lee, Juerg H Beer
Journal: Circulation (2022)

Introduction: Age-related gut microbiota alteration may underpin vascular disease. Yet, little is known about the role of cardiovascular disease-linked gut microbial metabolite phenylacetyl glutamine (PAG) in vascular aging. Hypothesis: 1) PAG promotes endothelial senescence via epigenetic and SASP modulation; 2) Acetate rescues PAG-induced endothelial senescence and impaired angiogenesis. Methods: We quantitated plasma concentrations of PAG and its precursor phenylacetic acid (PAA) in old and young healthy humans (&gt;65 vs. 18-35 years, n=41-45) and mice (24 vs. 3 months, n=6) by LC-MS/MS. Fecal acetate was measured by HPLC-RI. We then treated proliferating human aortic endothelial cells (PEC) with PAA+Glutamine (for PAG production) to examine its effects on cellular senescence, epigenetic and SASP state, mitochondrial respiration, and angiogenesis. Results: We showed markedly higher plasma PAA and PAG concentrations in old humans and mice vs. young ones. Yet, fecal acetate level was significantly lower in old vs. young mice. PAG significantly induced senescence (increased SA-β-gal positive cells and transcripts p16, p19, p21) and mitochondrial ROS production in PEC associated with upregulated SASP (IL1α, IL1β, TNF-α and adhesion molecule VCAM-1), and reduced mitochondrial respiration. PAG markedly reduced angiogenesis (endothelial sprouting and tube formation) accompanied by decreases in CaMKKβ T286 and histone deacetylase 4 (HDAC4 S632 ) phosphorylation, histone 3 (H3) acetylation, and the subsequent Mef2A-mediated eNOS S1177 phosphorylation. By contrast, acetate (3 μM) rescued senescence and impaired angiogenesis and mitochondrial function and reversed SASP and epigenetic alteration induced by PAG in PEC. Conclusions: We conclude that acetate regulates the aging gut microbial metabolite PAG-induced SASP and epigenetic alteration, by which rescues endothelial senescence and represents a potential vascular regenerative strategy.
Abstract 10242: Right Atrial Function and Fibrosis in Relation to Successful Atrial Fibrillation Ablation
Authors: Luuk H Hopman, Julia Visch, Pranav Bhagirath, Anja van der Laan, Mark Mulder, Orod Razeghi, Michiel Kemme, Steven A Niederer, Cornelis Allaart, marco J gotte
Journal: Circulation (2022)

Introduction: Atrial remodeling, characterized by changes in atrial structure and function, is central to the development and maintenance of atrial fibrillation (AF). Besides left atrial (LA) remodeling, right atrial (RA) remodeling may also contribute to AF perpetuation, and its presence may affect clinical outcome of AF ablation. Bi-atrial remodeling in patients with AF is rarely assessed and data on the presence of RA fibrosis, the relationship between RA and LA fibrosis, and possible association of RA remodeling with AF recurrence after ablation is limited. Methods: 110 AF patients undergoing initial pulmonary vein isolation (PVI) were included in the present study. Patients were in sinus rhythm during cardiac magnetic resonance (CMR) imaging performed prior to ablation. LA and RA volumes and function (volumetric and strain) were derived from cine CMR images. The extent of LA and RA fibrosis was assessed from 3D late gadolinium enhancement images. AF recurrence was followed-up for 12 months after PVI using either 12 lead ECGs or Holter monitoring. Results: Arrhythmia recurrence was observed in 39 patients (36%) after the 90-day blanking period, occurring at a median of 181 (IQR: 122-286) days. RA remodeling parameters were not significantly different between patients with AF recurrence as compared to patients without AF recurrence after ablation, whereas LA remodeling parameters were (volume, emptying fraction and strain). LA fibrosis had a strong correlation with RA fibrosis (r=0.88, P &lt;0.001). Both, LA and RA fibrosis was not different between patients with and without AF recurrence. Conclusions: RA remodeling parameters were not predictive of AF recurrence after AF ablation. Bi-atrial fibrotic remodeling is present in AF patients and the amount of LA fibrosis had a strong correlation with the amount of RA fibrosis. The presence of bi-atrial fibrotic tissue may be an expression of disease state although no relation with AF recurrence after AF ablation was found.
Abstract 10665: The Glycemic and Insulin Levels Contribute to the Sympathetic Response to Exercise in Individuals With and Without Diabetes Mellitus
Authors: Takuto Hamaoka, Urs A Leuenberger, Cheryl Blaha, Jonathan C Luck, Jian Cui
Journal: Circulation (2022)

Introduction: Exaggerated responses in blood pressure (BP) and muscle sympathetic nerve activity (MSNA) during exercise are suggested to contribute to adverse cardiovascular events. The risk of developing cardiovascular disease is elevated in patients suffering from diabetes mellitus (DM) and pre-DM; however, the relationship between the sympathetic responses to exercise and the glycemic and insulin indices in DM and non-DM remain unclear.Hypothesis: We hypothesized that the magnitude of MSNA response to exercise is related with glycemic and insulin indices in DM and Pre-DM subjects. Method: Eleven clinically diagnosed T2DM patients (54.0 ± 2.7 yrs) and 20 non-DM subjects (58.6 ± 2.3 yrs, 10 pre-DM [5.7% ≤ HbA1c &lt; 6.5%] and 10 healthy subjects) were examined. All non-DM subjects, including pre-DM subjects, had no noted diseases and were not on any medication. Five DM patients were on antihypertensive agents. The BP and glycemic control in the DM patients was relatively well managed with medications (HbA1c, 6.8 ± 0.3 %) and were without other cardiovascular complications. Beat-by-beat BP, heart rate, and MSNA were recorded simultaneously under a resting condition and during static handgrip exercise (HGe) at 30% maximal voluntary contraction until fatigue. Results: Resting MSNA in DM was lower than non-DM subjects (P &lt; 0.05). However, the MSNA response (i.e., the change) to HGe in DM was higher than non-DM (139% vs 75% increase, P &lt; 0.05). The MSNA response to HGe was significantly correlated (R = 0.59, P &lt; 0.05) with fasting blood glucose (FBG) across all subjects. Even in only pre-DM subjects, the MSNA response to HGe was significantly correlated with glucose/insulin indices (vs. FBG, R = 0.91, P &lt; 0.05; vs. blood insulin concentration, R = 0.84, P &lt; 0.05). Conclusion: In the present study, the MSNA response to exercise in T2DM patients was greater than that in non-DM subjects. Importantly, the MSNA response to exercise was correlated with glycemic/insulin indices over a broad range. This relationship was observed even before the development of DM. We speculate that the altered glycemic/insulin levels may contribute to the exaggerated sympathetic response to stress and in turn, contribute to the higher risk of cardiovascular diseases in these individuals.
Abstract 10366: Ep3 Receptor Contributes to Renal Ischemia and Inflammation During Development of Renal Pathologies and Hypertension in Pgis Deficient Mice
Authors: Yineng Xu, Jiahui Ge, Tingting Guo, Jinwei Guo, Rui Lin, Xiangzhai Tan, Gang Yu, Xijian Chen, Jing Leng, Ruhui Zeng, Dong He, Kaiqi Xie, Bin Liu, yingbi zhou
Journal: Circulation (2022)

Introduction: Abnormalities in prostacyclin synthase (PGIS) cause hypertension and/or renal pathologies in humans and mice due to increased thromboxane A2 (TxA 2 ) produced by platelets and/or kidneys. However, the kidney, which is the key organ in blood pressure regulation, mainly produces prostaglandin E2 (PGE 2 ), which could evoke renal vasoconstriction via activating the E prostanoid receptor-3 (EP3) and the Tx prostanoid receptor (TP; the receptor of TxA 2 ). We hypothesized that increased PGE 2 in the kidney contributes to hypertension and renal pathologies in the above-mentioned disorders via activating the EP3 receptor. Methods: To unravel the effect of PGE 2 , we first generated mice deficient for both PGIS and EP3 ( Pgis -/- Ep3 -/- ) or both PGIS and cyclooxygenase-1 ( Pgis -/- Cox-1 -/- ). To further exclude the effect of TxA 2 produced by the platelet COX-1, chimeric mice with Cox-1 -/- in hematopoietic cells were created by bone marrow transplantations of Pgis -/- and Cox-1 -/- mice. Results: Significant increases in blood pressure and heart-to-body-weight ratio were observed in Pgis -/- mice compared with WT mice, which were secondary to renal inflammation and fibrosis. In contrast, Pgis -/- Ep3 -/- had less renal damage resulting in fewer cardiovascular disorders. Furthermore, compared with WT kidneys, Pgis -/- kidneys showed increased levels of PGE 2 without PGI 2 and TxA 2 production as measured with high performance liquid chromatography-mass spectrometry. EP3 deficiency drastically diminished the decrease in renal blood flow evoked by ACh in Pgis -/- perfused kidneys. Interestingly, Pgis -/- Cox-1 -/- mice, but not Pgis -/- mice engrafted with bone marrow cells from Cox-1 -/- mice, displayed a much smaller extent of renal fibrosis than Pgis -/- mice. Conclusions: Increased levels of PGE 2 in the kidney contribute to hypertension and renal pathologies in PGIS abnormalities via activating the EP3 receptor. Our findings suggest a novel mechanism for intrarenal PGE 2 regulation of blood pressure and renal hemodynamics.
Abstract 10273: Proteomic Analysis of Chronic Kidney Disease (CKD) in Heart Failure With Preserved Ejection Fraction (HFpEF)
Authors: Qasim Jehangir, Chenao Qian, Jordana B Cohen, Oday Salman, Payman Zamani, Christina Ebert, Danielle Greenawalt, Ashok Dongre, Lei Zhao, Ching-Pin Chang, David A Gordon, Francisco Ramirez-Valle, Thomas P Cappola, Julio A Chirinos
Journal: Circulation (2022)

Introduction: CKD is highly prevalent in HFpEF and is associated with increased morbidity and mortality. The biologic correlates of CKD in HFpEF are not well understood. We conducted a plasma proteomics analysis to assess biologic pathways associated with CKD in HFpEF. Methods: We utilized biosamples from TOPCAT for de novo measurements of 4776 plasma proteins using the SomaScan (version 4) proteomic assay, among 218 participants enrolled in the Americas. Linear regression and pathway analyses were used to study the relationship of proteins and pathways to the estimated glomerular filtration rate (eGFR). All regression estimates are standardized (per unit increase in z score) to facilitate comparisons. Results: After correction for multiple comparisons, we identified 73 proteins associated with eGFR. The strongest positively associated proteins were contactin-4, contactin-1, laminin-2, tenascin-X, and neuropilin-2. Proteins with the strongest negative association were transmembrane emp24 domain-containing protein 10, desmocollin-2, beta-2-microglobulin, neutrophil gelatinase-associated lipocalin, and cystatin C ( Figure 1 ). Biologic pathways associated with eGFR included complement system, acute phase response signaling, apoptosis, lysosomal expression and regulation, inflammation, fibrosis, chondroitin and dermatan sulfate degradation, notch signaling, and gluconeogenesis ( Figure 2 ). Conclusions: Using a broad proteomics approach, we identified novel biomarkers and pathways associated with renal dysfunction in HFpEF. Further research is required to assess whether targeting these pathways can ameliorate renal dysfunction in HFpEF patients.
Abstract 10237: Targeting on Nrf2/Sesn2 Signaling to Rescue Cardiac Dysfunction During High Fat Diet-Induced Obesity
Authors: Meredith Krause-Hauch, Julia R Fedorova, Linda Ines Zoungrana, Hao Wang, Zehui Li, Mohammad Fatmi, Kayla Davitt, Di Ren, Ji Li
Journal: Circulation (2022)

Introduction: Obesity increases the chances of developing cardiovascular disease and strokes. The overabundance of adipose tissue that occurs in obese individuals increases oxidative stress, which trigger upregulation of antioxidant proteins, Sesn2 and Nrf2. Hypothesis: Obesity-related oxidative stress triggers cardiac Sesn2 and Nrf2 to function in cardioprotective properties. Methods: Cardiomyocyte specific Sesn2 knock out (cSesn2 -/- ) and overexpression (tTa-tet-Sesn2) C57BL/6J mice, and their wildtype littermates (Sesn2 f/f and tet-Sesn2) were subjected to either a high fat diet (HFD) or chow diet. Seahorse XF Analyzer for mitochondrial function and IonOptix Calcium and Contractility System for cardiomyocytes contractile functions. Results: The inducible cardiomyocyte overexpression of Sesn2 (tTa-tet-Sesn2) versus tet-Sesn2 mice gained less weight with HFD. Echocardiography data showed no significant differences in systolic function between tet-Sesn2 and tTa-tet-Sesn2 with HFD or chow diet. However, HFD induced diastolic dysfunction of tet-Sesn2 but not tTa-tet-Sesn2 hearts. Intriguingly, cardiac Nrf2 levels were upregulated in tTa-tet-Sesn2 but not tet-Sesn2 hearts with HFD. Conversely, cSesn2 -/- versus Sesn2 f/f showed lower Nrf2 levels and greater cardiac dysfunction with HFD. MitoSOX staining demonstrated that tTa-tet-Sesn2 versus tet-Sesn2 maintain redox homeostasis in the heart with HFD, while cSesn2 -/- versus Sesn2 f/f showed more reactive oxygen species (ROS) in the heart with HFD. Mitochondrial respiration was impaired in obese cSesn2 -/- versus Sesn2 f/f cardiomyocytes. Moreover, the contractility and transient calcium flux signaling was impaired in obese cSesn2 -/- versus Sesn2 f/f cardiomyocytes. tTa-tet-Sesn2 versus tet-Sesn2 cardiomyocytes demonstrated resistance to HFD-induced contractile dysfunctions, impaired calcium homeostasis and activation of the inflammation-related signaling NF-κB. Conclusions: Sesn2 and Nrf2 modulate redox homeostasis and inflammatory response during obesity pathogenesis. There is a feedforward loop relationship between Sesn2 and Nrf2 in the heart with HFD-induced obesity. Cardiac Sesn2/Nrf2 signaling ameliorates cardiac dysfunction caused by obesity.
Abstract 12699: Ferroptosis Inhibition Combats Pulmonary Vascular Remodeling and Improves RV-PA Coupling in Monocrotaline Rats
Authors: Neal Vogel, Sasha Z Prisco, Kurt W Prins
Journal: Circulation (2022)

Introduction: Ferroptosis is an iron-dependent, non-apoptotic, highly inflammatory form of cell death. Ferroptosis is initiated by lipid peroxidation, and therefore ferroptotic cell death is sensitive to metabolic derangements, altered iron homeostasis, and oxidative stress. In the systemic circulation, ferroptosis inhibition improves endothelial cell function, but the role of ferroptosis in pulmonary arterial hypertension, a disease characterized by pulmonary arterial endothelial cell metabolic derangements and abnormal redox balance, is not well understood. Methods: Male Sprague Dawley rats were randomized into 3 groups: control, monocrotaline-vehicle (MCT-V), and MCT rats treated with a small molecule ferroptosis inhibitor (MCT-FI). Treatment started 14 days after MCT to improve translational potential. Pulmonary vascular disease severity, cardiomyocyte hypertrophy, and right ventricular (RV) function were assessed with histology, echocardiography, and closed-chest pressure-volume loop analysis. Results: Ferroptosis inhibition blunted pulmonary vascular disease severity as right ventricular systolic pressure and effective arterial elastance were significantly reduced and pulmonary arterial acceleration time was increased. Histological analysis demonstrated RV cardiomyocyte cross sectional area was lowered by ferroptosis antagonism. When evaluating RV function, echocardiography revealed an improvement in both tricuspid annular plane systolic excursion and RV free wall thickening while pressure-volume loop analysis showed RV-pulmonary artery (PA) coupling was restored by ferroptosis inhibition. Conclusions: Small molecule-mediated disruption of ferroptosis combated pulmonary hypertension and restored RV-PA coupling in MCT rats.
Abstract 10204: Single Cell Transcriptomics of Multiple Organ Sources to Develop Better Cell Grafts for Therapeutic Angiogenesis
Authors: Oto Inoue, Soichiro Usui, Chiaki Goten, Ayano Nomura, Daiki Hashimuko, Kosei Yamaguchi, Yusuke Takeda, Hiroshi Ootsuji, Shinichiro Takashima, Juan Sanchez-Gurmaches, Masayuki Takamura
Journal: Circulation (2022)

Introduction: To develop better cell therapy to combat cardiovascular disease (CVD), a greater number of cell markers or populations should be tested for their regenerative potentials. We applied single cell RNA-sequencing (scRNA-seq) analysis of multiple organs to identify attractive cell subsets for therapeutic angiogenesis. Methods: We revisited scRNA-seq datasets of various human organs. Transcriptomic data were normalized and analyzed for dimension reduction, cell clustering, and gene ontology. The screened cell population was sorted, cultured, and transplanted into a nude mice model of limb ischemia. Furthermore, AT of CVD patients ( n =40) was evaluated for the cell subset by flowcytometry. Results: We analyzed three well-known sources of cell therapy including bone marrow, adipose tissue (AT), and umbilical-cord blood. After clustering, lineage negative mesenchymal cell clusters were compared their expression of pro/anti-angiogenic factors. Interestingly, AT showed the most prominent expression of both pro- and anti-angiogenic factors ( Fig.A ). Then, we divided AT stromal cells into pro- and anti-angiogenic clusters. From this clustering, 17 markers were screened as specific for pro-angiogenic cluster ( Fig.B ). Subsequently, we identified a receptor CD271 as top candidate for angiogenic cell isolation. CD271 + cells showed enhanced angiogenic capacity in cell therapy experiments when compared to CD271 - cells. Furthermore, we detected long-term engraftment (PKH26) and increased number of proliferating host tissue cells using EdU labeling ( Fig.C ). Finally, we found CD271 + cells were significantly reduced and deteriorated in CVD patients with insulin resistance or higher Lp(a) ( Fig.D ). Conclusions: CD271 + cells from AT of metabolically healthy donors appears as an attractive for therapeutic angiogenesis. ScRNA-seq analysis is a potent tool to accelerate cell therapy field to find better cell populations and appropriate resources.
Abstract 10978: Sleep Duration and Risks of Cardiovascular Disease Onset and Mortality Among Patients With Type 2 Diabetes
Authors: Han Han, Ying Wang, Tongtong Li, Chengwu Feng, Catherine Kaliszewski, Yang Su, Yinfan Wu, Jian Zhou, Liang Wang, Geng Zong
Journal: Circulation (2022)

Introduction: Patients with type 2 diabetes (T2D) may have inadequate (insufficient or excessive) sleep which could accelerate CVD onset, but existing evidence from prospective studies is limited. Hypothesis: We hypothesized that inadequate sleep duration would be associated with higher risks of CVD incidence and mortality among patients with T2D. Methods: This prospective study included 19,345 participants with T2D who were free of CVD and cancer at baseline from the UK Biobank. Sleep duration was obtained at baseline using questionnaires. Cox proportional hazards regression models were used to examine the association of sleep duration with CVD events. Results: During an average follow-up of 11.0-12.0 years, we documented 2,219 incident CVD cases (1,555 CADs and 673 strokes) and 652 CVD deaths. Compared with those sleeping for 7-8 h/day, the multivariable-adjusted hazard ratios (95% confidence intervals) of sleeping for ≤5 and ≥10 h/day were 1.39 (1.19-1.61) and 1.38 (1.13-1.68) for incident CVD, 1.26 (1.04-1.51) and 1.23 (0.95-1.57) for CAD, 1.68 (1.30-2.16) and 1.75 (1.27- 2.42) for stroke, and 1.36 (1.02-1.80) and 1.94 (1.42-2.63) for CVD mortality. These results largely remained similar in sensitivity analyses that aimed to address potential reverse causation and in the joint analysis of sleep duration and metabolic control or diabetes severity status. Conclusions: Our findings showed inadequate sleep duration was independently associated with increased risks of CVD onset and death among patients with T2D.
Abstract 10642: Hemodynamics One Year Post Pediatric Heart Transplant Are Associated With Pre-Transplant Variables and Correlate With Mortality
Authors: Hanna John J Tadros, Susan W Denfield, Athar Qureshi, Kyle Hope, Kriti Puri, Jack Price, Hari P Tunuguntla, Swati Choudhry, Iki Adachi, William Dreyer, Joseph Spinner
Journal: Circulation (2022)

Background: Hemodynamics (HDS) after pediatric heart transplant (PHT) are understudied and may predict future outcomes. We sought to identify variables associated with normalization (NML) of HDS in the 1 st year post-HT and determine association with post-HT outcomes. Methods: HDS were collected from patients who underwent HT between 2013-2020 without a history of pre-HT mechanical support and with at least 3 catheterizations in the 1st year post-HT. NML was defined as 2 consecutive catheterizations with pulmonary vascular resistance index (PVRi) &lt; 3Wu/m 2 , cardiac index (CI) &gt; 2.5L/min/m 2 , and pulmonary wedge pressure (PCWP) &lt;12 mmHg. Freidman repeated measure was used to assess HDS over time and Cox regression associations with NML and long-term mortality. Results: Among 97 patients included, PCWP decreased, CI increased, and PVR remained stable over the 1 st year post-HT (Figure 1A). Only 50% (n=47) had NML by 1 year. Median time to NML was 181 days (IQR 355). Mean PCWP and PVR over the 1st year were higher in non-NML vs NML patients (13.3 vs. 10.8, p&lt;0.001; 2.2 vs. 1.8, p=0.024). On multivariate analysis, patients with retransplant (HR 2.91, p&lt;0.001) and normal HDS at the 1 st post-HT catheterization (HR 4.08, p&lt;0.001) were more likely to have NML, while those with pre-HT congenital heart disease (HR 0.46, p=0.043) were less likely (Table 1/Figure 1B). NML by 1 year-post-HT was not associated with long-term mortality (p=0.794), but lower CI (HR 0.10, p=0.048) and higher PCWP (HR 1.44, p=0.006) at 1 year post-HT were associated with mortality. Conclusion: Only half of PHT recipients have NML of HDS at 1-year post-HT. The CI and PCWP at 1 year post-HT correlated with long-term mortality.
Abstract 12709: Characterization of Growth Hormone Releasing Hormone Receptor During Cardiomyogenesis
Authors: Amarylis Wanschel, Konstantinos Chatzistergos, Alessandro Salerno, Krystalenia Valasaki, Stefan Kurtenbach, Wayne Balkan, Derek Dykxhoorn, Andrew Schally, Joshua M Hare
Journal: Circulation (2022)

Introduction: Differentiation and expansion of cardiomyocytes from human-induced pluripotent stem cells is a poorly understood process, and the signals promoting differentiation of cardiomyocytes toward specific cell fates are not well defined. Here we show that the growth hormone-releasing hormone receptor (GHRH-R) signaling pathway controls this differentiation process and cell fate. Hypothesis: Stimulation of hPSCs with GHRH promotes β-catenin stabilization through the GH/IGF1 axis. The presence of cell-surface GHRH-R differentiates between atrio-ventricular cardiomyocytes and non-cardiomyogenic cardiac cells, including coronary vascular, neuronal and pacemaker cells, such that selecting for GHRH-R allows for the elimination of pacemaker cells and derivation of a pure population of atrio-ventricular cardiomyocytes. Methods: Using RNA-seq to comprehensively characterize the GHRH-R signaling pathway, we identified that NKX2-5, a transcription factor involved in progenitor specification and differentiation into atrio-ventricular cardiomyocytes, is upregulated in response to GHRH. Results: GHRH-R signaling also upregulated HIF-1α via the PI3k/Akt/mTOR pathway to enhance NKX2-5 transcription and stimulate a Warburg-like effect in developing cardiomyocytes. Conclusions: Together these findings provide crucial insights into human stem cell differentiation and offer a translationally useful tool to optimize the development of pure cardiomyocyte preparations derived from induced pluripotent stem cells.